Sex steroid hormones such as progestin, oestrogen are involved in the growth and development of reproductive system and secondary sex characteristics. Growing evidences suggests that these hormones also play critical roles in the development and progression of tumors of the prostate, ovary, breast, liver, endometrial and skin (Lens, M. et al. Cancer Causes Control. 2008, 19, 437-442; Driscoll, M. S. et al. J. Am. Acad. Dermatol. 2007, 57, 919-931;). For example, the role of estrogen in the development and growth of breast cancer is well established and based on that, drugs against breast cancer have been developed which target Estrogen Receptor (ER) (Freedman, R. A. et al. Breast. 2010, 19, 69-75;). However, the role of progestins in breast cancer remains contradictory as some reports suggest that progestins such as Medroxyprogesterone acetate (MPA) and megestrol acetate may be used against breast cancer (Hultborn, R. et al. Wallgren, Acta. Oncol. 1996, 35, 75;), while other reports showed antiprogestins as an effective treatment option for breast cancer (Edwards, D. P. et al. J. Steroid Biochem. Mol. Biol. 1995, 53, 449-458;). Moreover, it is also demonstrated that both progesterone and antiprogesterone (mifepristone) can exert anti-proliferative effect on non-reproductive tissues regardless of progesterone receptor (PgR) expression status (Ivarsson, K. et al. Gynecol Oncol. 2001, 82, 116-121;). Given the conflicting role of progesterone and antiprogestins in cancer, it is challenging to develop progesterone-based modified therapeutics that work against both PgR-positive and PgR-negative cancer but at the same time remain non-toxic towards healthy cells.
Recently it has been demonstrated that progestin like MPA (progesterone modified molecule), a potential candidate for breast cancer therapeutics, but often fail to exert its anticancer activity due to persistent activity of the PI3K/AKT [phos-phatidylinositol 3-kinase (PI3K)] survival pathway (Riggio, M. et al. Carcinogenesis. 2012, 33, 509-518;). PI3K/AKT pathway, a key regulator in the event of cell proliferation, cell cycle, survival, apoptosis, migration and angiogenesis is frequently altered in many cancers (Kao, G. D. et al. J. Biol. Chem. 2007, 282, 21206-21212;). The activation of AKT by PI3K resulted in the activation of Mdm2, which ubiquitinylate p53, a key tumor suppressor protein, for proteasomal degradation (Surget, S. et al. Onco. Targets. Ther. 2013, 7, 57-68;). Hence, the stability or status of p53 expression in cancer cells is a well-known marker to adjudge the effect of anticancer therapeutics.
Angiogenesis plays a critical role in the formation of new blood vessels from pre-existing blood vessel (Potente, M. et al. Cell. 2011, 146, 873-887). Apart from its fundamental role in normal physiological functions like embryonic development, wound healing, reproduction, etc., it also contributes heavily in tumor growth, and metastasis. Earlier experiments demonstrated anti-angiogenic effect of MPA, (Abulafia, O. et al. Gynecol. Oncol. 1999, 72, 193-198; Ashino-Fuse, H. Int. J. Cancer. 1989, 44, 859-864). Indicating that properly functionalized progesterone or its derivatives may lead to the development of new anti-angiogenic molecules.
To date, no literature has been reported regarding the use of cationic progesterone molecule as a potent anticancer therapeutics. However, there are some reports which demonstrate the anticancer property of progesterone (Leo, J. C. et al. Int. J. Cancer. 2005, 117, 561-568;) and by its metabolites (Weibe, J. P. et al. Breast Cancer Res. 2013, 15, R38). Progesterone has also been used in anticancer treatment along with other anticancer drug such as calcitriol (Lee, L. R. et al. Cancer Prev Res. 2013, 6, 731-743), Tamoxifen (Lee, J. Y. et al. Oncol Rep. 2012, 27, 87-93; Gaston, K. et al. Patent No. WO2001082910 A2, 8 Nov. 2001) and Estrogen products (Rodriguez, G. C. U.S. Pat. No. 6,977,250 B2, 20 Dec. 2005)